U.S. patent application number 10/561631 was filed with the patent office on 2007-03-29 for oil emulsion for postnatal hormone substitution.
Invention is credited to Sonja Bromer, Jorg Nehne, Frank Pohlandt.
Application Number | 20070071777 10/561631 |
Document ID | / |
Family ID | 33395816 |
Filed Date | 2007-03-29 |
United States Patent
Application |
20070071777 |
Kind Code |
A1 |
Bromer; Sonja ; et
al. |
March 29, 2007 |
Oil emulsion for postnatal hormone substitution
Abstract
The invention relates to a process for the preparation of
hormone-containing oil emulsions (lipid emulsions), an isotonic oil
emulsion obtainable by such process, and the use of the emulsion
according to the invention for the preparation of a medicament for
intravenous administration, especially for postnatal hormone
substitution in premature babies and for the treatment of
neurological damage after strokes.
Inventors: |
Bromer; Sonja; (Melsungen,
DE) ; Nehne; Jorg; (Guxhagen, DE) ; Pohlandt;
Frank; (Ulm, DE) |
Correspondence
Address: |
CHRISTIE, PARKER & HALE, LLP
PO BOX 7068
PASADENA
CA
91109-7068
US
|
Family ID: |
33395816 |
Appl. No.: |
10/561631 |
Filed: |
June 15, 2004 |
PCT Filed: |
June 15, 2004 |
PCT NO: |
PCT/EP04/51114 |
371 Date: |
October 31, 2006 |
Current U.S.
Class: |
424/400 ;
514/170 |
Current CPC
Class: |
A61K 31/57 20130101;
A61P 5/30 20180101; A61P 5/34 20180101; A61K 31/565 20130101; A61P
25/28 20180101; A61K 9/1075 20130101; A61P 5/24 20180101 |
Class at
Publication: |
424/400 ;
514/170 |
International
Class: |
A61K 31/57 20060101
A61K031/57; A61K 31/56 20060101 A61K031/56; A61K 9/00 20060101
A61K009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 18, 2003 |
EP |
03013790.5 |
Claims
1. A process for the preparation of isotonic oil emulsions
containing estrogen a and progestagen for intravenous
administration, comprising the steps of: (A) dissolving at least
one of the hormones estrogen and progestagen in an oil phase; and
(B) emulsifying the oil phase in the aqueous phase; in the presence
of an emulsifier.
2. A hormone-containing isotonic oil emulsion for intravenous
administration comprising progestagens and estrogens, obtainable by
the process according to claim 1.
3. The hormone-containing isotonic oil emulsion for intravenous
administration according to claim 2, comprising progestagens and
estrogens in a ratio of from 2:1 to 200:1.
4. The oil emulsion according to claim 2 or 3, characterized in
that the emulsion contains from 0.005 to 0.5% by weight of an
estrogen and from 0.05 to 5% by weight of a progestagen, based on
the total composition.
5. The oil emulsion according to any of claims 2 to 4,
characterized in that said estrogen is estradiol and said
progestagen is progesterone.
6. The oil emulsion according to any of claims 2 to 5,
characterized in that said oil phase comprises medium chain
triglycerides (MCT) having a chain length of from 6 to 12,
preferably from 8 to 10, carbon atoms.
7. The oil emulsion according to any of claims 2 to 6,
characterized by containing up to 1.5% by weight of the emulsifier,
based on the total composition.
8. Use of the isotonic oil emulsion according to any of claims 2 to
7 for preparing a medicament for intravenous administration of
estrogen and progestagen for postnatal hormone substitution in
premature babies.
9. Use of the isotonic oil emulsion according to any of claims 2 to
7 for preparing a medicament for the treatment of neurological
damage after strokes.
10. A process for hormone substitution in premature babies by using
the isotonic oil emulsion according to any of claims 2 to 7.
11. A process for the treatment of neurological damage after
strokes by using the isotonic oil emulsion according to any of
claims 2 to 7.
Description
[0001] The invention relates to a process for the preparation of
hormone-containing oil emulsions (lipid emulsions), an isotonic oil
emulsion obtainable by such process, and the use of the emulsion
according to the invention for the preparation of a medicament for
intravenous administration, especially for postnatal hormone
substitution in premature babies and for the treatment of
neurological damage after strokes.
TECHNICAL BACKGROUND OF THE INVENTION
[0002] During pregnancy, the plasma levels of 17-.beta.-estradiol
(an estrogen) and progesterone (a progestagen) increase up to 100
fold. This enhanced synthesis of estrogen and progesterone serves
for maintaining pregnancy, inter alia. From examinations of cord
blood at different times during pregnancy, it can be seen that the
fetus is also exposed to these high plasma levels. There are clear
indications of the fact that the fetal development of various
organs, such as the lungs, bones and brain, depends on estrogen and
progesterone. Full term childbirth occurs after 40 weeks of
pregnancy, after which a rapid decrease of estradiol and
progesterone occurs in both the newborn and the mother. This
decrease of the hormone levels is presumably co-responsible for the
depression from which women frequently suffer after childbirth.
[0003] In the Federal Republic of Germany, from 6 to 7% of all
newborns are premature babies, i.e., the day of birth is before the
end of the 37th week of pregnancy. Thus, the rapid decrease of the
plasma levels of estradiol and progesterone occurs at an earlier
time during fetal development, which might have consequences for
the still immature organs. Even today, immature lung function in
extremely small premature babies (below 1000 g birth weight) is
still a frequent cause of newborn mortality. Follow-up studies on
former premature babies also show that their neurological
development is adversely affected on a long-term basis.
[0004] Studies on 30 premature babies made by Trotter et al. at the
children's hospital of the University of Ulm (published in J. Clin.
Endocrinol. Metab. 84, 4531-4355 (1999)) show that premature babies
can benefit from a maintenance of the high plasma levels of
estradiol and progesterone. Premature babies were continuously
intravenously administered a diluted lipid emulsion which contained
the hormones 17.beta.-estradiol and progesterone in amounts
sufficient to maintain the plasma levels as found in the womb. It
was found that the premature babies exhibited a better median bone
mineralization. In addition, it could be observed that the
additional administration of oxygen was less frequently necessary
in hormone-treated premature babies at the age of 28 days. This
observation can be attributed to a better lung maturation. The
intravenous administration of the sexual hormones was effected over
an average of 3 weeks.
[0005] In the above described study, the hormones estrogen and
progesterone in an alcoholic solution were added to the lipid
emulsion which was manufactured by the company Pharmacia &
Upjohn and sold under the trade name of Intralipid.RTM., and
administered in this form. The oil phase of Intralipid.RTM.
consists of 100% soybean oil in the form of long-chain
triglycerides.
[0006] More exact chemical analyses show that there are
considerable uncertainties in the admixing of the sexual hormones
with Intralipid.RTM.. For example, it is unclear whether the
mixture of the steroids in Intralipid.RTM. is physically stable at
all. However, experiments with radioactively labeled hormones
showed that a considerable fraction of the hormones to be applied
is absorbed at the surface of the infusion systems and feed ducts.
This necessarily results in problems and uncertainties with respect
to the availability of the intravenously administered hormones to
the infant.
[0007] In addition, in the course of the above described studies it
was found that the administration of relatively large amounts of
hormone-containing oil emulsion resulted in comparatively low
hormone levels in the premature Baby's blood. Therefore, to achieve
the desired serum levels, relatively high amounts of oil emulsions
have had to be administered to the premature babies to date. These
high amounts resulted in an undesirable oil and liquid load on the
premature baby. Moreover, the administration of alcoholic
compositions to premature babies is not a preferred treatment
method.
[0008] In addition, follow-up examination at the corrected age of
15 months of the premature babies treated in the pilot study
reveals a positive influence on the neurological development
(published in J. Clin. Endocrinol. Metab. 86, 601-603 (2001)).
[0009] A transepidermal treatment with the corresponding hormones
is possible in principle, but can be started only 2 to 3 weeks
after birth for developmental reasons.
[0010] The presently available results show a positive influence of
the hormone treatment on the target criteria, i.e., lung maturation
and development, neurological development and bone mineralization,
i.e., an overall improvement of the premature babies' maturation.
In addition, the parenterally administered lipid emulsion also
serves mere nutrition purposes by supplying oil in an intravenously
tolerable dosage form to the premature organism for which enteral
food supply is often difficult.
[0011] Further, Alkayed et al. in Stroke 31, 161 (2003), describe
the positive influence of subcutaneously administered estrogens and
progesterones on the condition of stroke patients.
[0012] Therefore, the object of the invention is to provide
parenterally administrable oil emulsions which result in as high as
possible an enrichment of the hormones (availability) in the
premature baby's blood with a minimum oil and volume load, in
contrast to the emulsions described in the prior art.
[0013] Surprisingly, it has been found that the parenteral
administration of an oil emulsion containing estradiol and
progesterone in the preparation of which the hormones are dissolved
in the oil phase before the emulsification results in clearly
higher serum levels as compared to the administration of emulsions
to which the hormones are directly added.
DESCRIPTION OF THE FIGURES
[0014] FIG. 1 describes the estradiol plasma level at the
individual measuring times (day 1, 3, 7, 14) in the premature
babies treated with the different emulsions.
[0015] FIG. 2 describes the progesterone plasma level at the
individual measuring times (day 1, 3, 7, 14) in the premature
babies treated with the different emulsions.
DESCRIPTION OF THE INVENTION
[0016] The present invention relates to a process for the
preparation of isotonic oil emulsions containing estrogen and
progestagen for parenteral, preferably intravenous, administration
comprising the steps of: [0017] (A) dissolving at least one of the
hormones estrogen and progestagen in an oil phase; and [0018] (B)
emulsifying the oil phase in the aqueous phase; in the presence of
an emulsifier.
[0019] Another embodiment of the invention relates to a
hormone-containing isotonic oil emulsion for intravenous
application which can be obtained by the above process. In a
preferred embodiment, progestagen and estrogen are in a ratio of
from 2:1 to 200:1 in the emulsion.
[0020] The o/w emulsions according to the invention are suitable
for parenteral, especially intravenous, administration.
Accordingly, a third embodiment of the invention relates to the use
of the above isotonic oil emulsion for intravenous administration,
especially for postnatal hormone substitution in premature
babies.
[0021] In connection with the present invention, the terms "oil"
and "lipid" have the same meaning and are therefore used
interchangeably. This group of substances includes, in particular,
triglycerides, partial glycerides and fatty acid residues as well
as their mixtures.
[0022] In particular, the oil emulsions according to the invention
are suitable for processes for the preparation of medicaments for
the parenteral administration of estrogens and progestagens,
preferably for postnatal hormone substitution in premature
babies.
[0023] Further embodiments of the invention can be seen from the
dependent claims.
[0024] The postnatal substitution of progestagen and estrogen aims
at the maintenance of intra-uterine plasma levels (plasma level in
utero). In order to keep the deviation from the intra-uterine
plasma levels as low as possible after birth, it is desirable that
such levels are reached as quickly as possible after the beginning
of the substitution.
[0025] Hormone substitution is not restricted to premature human
babies, but may also be applied to animals, preferably mammals.
[0026] The oil emulsions according to the invention have a clearly
improved availability of the hormones contained therein as compared
to that of an oil emulsion of the prior art.
[0027] As compared to prior art emulsions, the oil emulsion
according to the invention results in a faster increase of the
hormone level and in a higher estrogen end concentration while the
volume and oil loads are lower.
[0028] In addition, the oil emulsions according to the invention
have an improved stability as compared to the alcoholic hormone
solutions of the prior art.
[0029] The critical step of the process for the preparation of the
oil emulsions according to the invention is the dissolution of the
hormones estradiol and progesterone in the oil phase before the oil
phase is emulsified with the aqueous phase. Basically, both
hormones are dissolved in the oil phase. In another embodiment
according to the invention, only one of the hormones, preferably an
estrogen, is dissolved in the oil phase while the progestagen is
added to the aqueous phase and/or to the finished emulsion.
[0030] The hormones used in connection with the present invention
are those which also occur in utero. A distinction is made, in
particular, between the follicular hormones (estrogens) and the
hormones of the yellow body (progestagens).
[0031] The follicular hormones which are important in connection
with the present invention are estrone, 17.beta.-estradiol and
estriol and their derivatives. Due to its high estrogenic activity,
17.beta.-estradiol is of particular importance for the present
invention.
[0032] The progestagens used in connection with the present
invention are pregnelonone, progesterone, medroxyprogesterone and
their pharmaceutically acceptable derivatives, progesterone being
used preferably in connection with the present invention.
[0033] One embodiment of the invention relates to the combination
of estrone with pregnelonone and/or progesterone, another to the
combination of estriol with pregnelonone and/or progesterone. An
alternative, particularly preferred embodiment relates to the
combination of 17.beta.-estradiol and/or pregnelonone and/or
progesterone, especially with progesterone. In both alternatives,
medroxyprogesterone may be additionally contained, or
medroxyprogesterone may be substituted for pregnelonone and/or
progesterone. Thus, more than two hormones may also be combined
according to the invention.
[0034] The lipid emulsions according to the invention have hormone
concentrations which, when accordingly employed, result in plasma
levels in the premature baby as would have been to be expected in
the womb. Consequently, the lipid emulsion according to the
invention comprises between 0.005 and 0.5% by weight, preferably
between 0.01 and 0.2% by weight, more preferably between 0.05 and
0.1% by weight, of at least one estrogen, and between 0.05 and 5%
by weight, preferably between 0.1 and 2% by weight, more preferably
between 0.5 and 1% by weight, of at least one progestagen, based on
the total composition (parent emulsion).
[0035] The ratio of progestagen to estrogen in the emulsion is from
2:1 to 200:1, preferably from 5:1 to 50:1, more preferably from
10:1 to 20:1.
[0036] For a better dosing of the oil emulsions, the parent
emulsions can be diluted, if necessary, with an appropriate amount
of water, preferably with up to the fourfold amount of water.
[0037] The lipid emulsions according to the invention are
preferably prepared from oils of vegetable origin (e.g., safflower
oil or soybean oil) and/or MCT and/or oils of animal origin.
Therefore, they can contain vegetable oil and/or medium-chain
triglycerides (MCT) and/or oils of marine origin (e.g., fish oils).
Such lipid emulsions are known to the skilled person from the prior
art.
[0038] Vegetable oils and especially the oils of soybean and
safflower are characterized by a high content of polyunsaturated
fatty acids of the .omega.-6 series (predominantly linolic acid,
18:2 .omega.-6), while their content of .omega.-3 fatty acids
(virtually exclusively as .alpha.-linolenic acid, 18:3 .omega.-3)
is low.
[0039] Medium-chain triglycerides (MCT) have a chain length of from
C.sub.6 to C.sub.14, a chain length of from C.sub.8 to C.sub.10
being particularly preferred.
[0040] The medium-chain triglycerides (MCT) administered with the
oil emulsions predominantly serve as an energy source. Medium-chain
triglycerides do not contain any unsaturated fatty acids at all,
and they thus contain neither .omega.-6 nor .omega.-3 fatty
acids.
[0041] The fish oils obtained from cold-water fish are
characterized by a high content of polyunsaturated fatty acids
(mainly eicosapentaenic acid, EPA, 20:5 .omega.-3 and
docosahexaenic acid, DHA, 22:6 .omega.-3), while their content of
.omega.-6 fatty acids is low. Suitable fish oils are those, for
example, which are obtained from cold-water fish industrially in
large amounts. Fish oils generally contain triglycerides of fatty
acids having from 12 to 22 carbon atoms. Particularly preferred are
highly purified fish oil concentrates which are obtained, for
example, from sardine oil, salmon oil, herring oil and/or mackerel
oil.
[0042] Therefore, one embodiment according to the invention relates
to an oil emulsion based on vegetable oil and/or MCT. This emulsion
may optionally contain fish oil.
[0043] The content of vegetable oil in the oil composition
according to the invention is at least from 50 to 100% by weight,
preferably from 70 to 100% by weight, more preferably from 90 to
100% by weight, based on the oil composition.
[0044] The beneficial effect of unsaturated fatty acids, especially
those of the .omega.-3 series, is known to the skilled person and
has been described, for example, in EP-A-0 311 091 and
DE-A-19648566. Also in connection with the present invention, the
use of oils which are rich in unsaturated fatty acids may be
advantageous.
[0045] The total oil content of the parent emulsion is between 1%
by weight and 30% by weight, preferably between 10% by weight and
20% by weight, based on the aqueous oil emulsion.
[0046] In addition to distilled water, the isotonic oil emulsion
may also contain the usual auxiliary agents and/or additives, such
as emulsifiers, co-emulsifiers, stabilizers, antioxidants and
isotonizing additives.
[0047] Physiologically acceptable emulsifiers, such as
phospholipids of animal or vegetable origin, are used as the
emulsifiers. Particularly preferred are purified lecithins,
especially egg lecithin or fractions thereof or the corresponding
phosphatides. The content of emulsifier is from 0.6 to 1.5% by
weight, preferably 1.2% by weight, based on the total emulsion.
[0048] Further, alkali salts of long chain C.sub.16 to C.sub.20
fatty acids may be used as co-emulsifiers. Their sodium salts are
particularly preferred. The co-emulsifiers are employed in a
concentration of from 0.005 to 0.1% by weight, preferably from 0.01
to 0.5% by weight, based on the total emulsion.
[0049] For stabilization and isotonization, the emulsion according
to the invention may contain from 1.0 to 8% by weight, preferably
from 2.0 to 6.0% by weight, more preferably from 2.2 to 2.6% by
weight, of a stabilizing or isotonizing additive, for example, a
polyhydric alcohol. In this connection, glycerol, glucose or
xylitol are preferred, glycerol being particularly preferred.
[0050] As antioxidants and thus for protection from peroxide
formation, the oil emulsion according to the invention may contain
tocopherols or physiologically acceptable tocopherol esters, e.g.,
alpha-tocopherol acetate, in an amount of from 10 to 1000 mg,
preferably from 25 to 200 mg, based on 100 g of oil.
[0051] Of course, no additives are used which have any undesirable
side effects or cause intolerances. In particular, fructose and
sorbitol are suspected to cause intolerances and are therefore
unsuitable in connection with the present invention. Further, the
oil emulsions according to the invention do not contain any
preservatives, such as benzyl alcohol.
[0052] The oil emulsions according to the invention are always
oil-in-water (o/w) emulsions in which the outer, continuous phase
consists of distilled water adapted for parental use.
[0053] The oil emulsion advantageously has a pH value of from 6.0
to 9.0, preferably from 6.5 to 8.5.
[0054] The isotonic aqueous lipid emulsions according to the
inventions can be prepared by known methods. The usual approach is
to mix the oils, the emulsifier and other auxiliary agents and
additives at first and then to add water while dispersing. The
water may optionally contain further water-soluble components
(e.g., glycerol). The thus obtained emulsion still has droplet
sizes of about 10 .mu.m. The average droplet size of the emulsion
must be reduced further by a further homogenization, e.g., by using
a high-pressure homogenizer. Preferred for parenteral, especially
intravenous, application are droplet sizes with a mean particle
diameter of from 0.5 .mu.m to 150 nm, more preferably from 1 .mu.m
to 100 nm. In addition, the solutions are to be sterilizable and
have a storage stability of at least 18 months.
[0055] In addition to the use of the isotonic oil emulsions
according to the invention for the parenteral, especially
intravenous, administration of estrogen and progestagen and, in an
alternative embodiment, for the preparation of a medicament for
this purpose, it has been found that the oil emulsions according to
the invention reduce the dying of nerve cells in the brain of
humans and animals, preferably mammals, and therefore may also be
employed for the preparation of medicaments for the treatment of
neurological damage after strokes (apoplexy). The oil emulsions
according to the invention may also be applied for prevention. In
such cases, oral administration of the oil emulsions is to be
preferred.
[0056] The isotonic oil emulsion according to the invention may be
employed in methods for hormone substitution in premature babies as
well as for the treatment of neurological damage after strokes.
[0057] The invention is illustrated by the following Examples, but
without being limited thereto.
EXAMPLES
Preparation of a Hormone-Containing Oil Emulsion
[0058] The hormones estradiol and progesterone are dissolved in the
oil heated at about 70.degree. C. under a nitrogen inert
atmosphere, optionally with the addition of tocopherol (=solution
I). The emulsifier (=phospholipids from egg) is dispersed in an
aqueous glycerol solution by means of an Ultra-Terrux.RTM. cell
homogenizer (Jahnke & Kunkle) (=component II). Solution I is
added to component II by using an Ultra-Terrux.RTM. cell
homogenizer. The pH value of the resulting o/w emulsion is adjusted
to about 8.5 by adding sodium oleate, followed by homogenization in
a high-pressure homogenizer under at least 400 kg/cm.sup.2.
[0059] After being filled into glass ampoules of suitable quality,
the emulsion is heat-sterilized by known methods. A sterile and
stable o/w emulsion with lipid droplets having an average oil
droplet size of less than 0.5 .mu.m and a storage stability of at
least 18 months results. TABLE-US-00001 TABLE 1 Preparation Example
1 2 3 4 I. Estradiol hemihydrate 0.66 g 0.66 g 0.60 g 0.60 g
Progesterone 6.00 g 6.00 g 6.00 g 6.00 g Medium-chain triglycerides
-- 100 g 100 g 200 g Purified soybean oil 200 g 100 g 80 g --
Highly purified fish oil -- -- 20 g -- .alpha.-Tocopherol -- -- 200
mg -- II. Purified phospholipids from: 12 g egg 12 g egg 12 g egg
12 g egg Glycerol 25 g 25 g 25 g 25 g Water for injection ad 1
liter ad 1 liter ad 1 liter ad 1 liter Sodium oleate 0.3 g 0.3 g
0.25 g 0.25 g
Application of a Hormone-Containing Oil Emulsion
[0060] The group of patients who were treated with a hormone
emulsion of the prior art consisted of 12 patients (premature
babies of <29 weeks of pregnancy, birth weight below 1000 g).
They were treated with a hormone emulsion consisting of 20% by
weight of Intralipid.RTM. (Pharmacia & Upjohn, Germany) diluted
with isotonic saline to 5% oil content, admixed with an ethanolic
solution of 0.15 mg/ml crystalline 17.beta.-estradiol and 1.4 mg/ml
progesterone,
[0061] The initial feeding was continuous and intravenous (i.v.) at
15 ml/kg/day. Both the hormone content of the emulsion and the
amount of liquid could be varied. This resulted in maximum liquid
loads of 25.8 ml/kg/day, median 18.8.
[0062] In a currently performed randomized double-blind study
relating to the influence of hormone substitution on additional
oxygen demand at the age of 28 days as the target criterion, 78
premature babies have already been recruited. In this study, the
hormone emulsion according to the invention (according to
Preparation Example 1, diluted with water for injection to an oil
content of 5%) or a placebo (hormone-free emulsion, oil content 5%)
was employed. Results from 52 patients relating to the estradiol
and progesterone plasma levels achieved are already available.
Without unblinding, it can be derived from the plasma levels that
25 patients were treated with a hormone-containing solution (verum
group). All patients were continuously administered i.v. 15
ml/kg/day of the emulsion according to the invention. From this
value, a mean hormone dosage of 2.47 mg/kg/day of estradiol and
22.5 mg/kg/day of progesterone can be derived.
[0063] The plasma levels of estradiol and progesterone on day of
life 1 (24 hours), 3, 7 and 14 under continuing hormone supply were
determined in both groups. The results of these studies are shown
in the following Table: TABLE-US-00002 TABLE 2 Prior art emulsion
Emulsion according to the invention Dosage Plasma level Dosage
Plasma level Hormone (mg/kg/day) (ng/ml)*.sup.) (mg/kg/day)
(ng/ml)*.sup.) P Estradiol 2.23 2.622 2.48 4.270 0.00038
Progesterone 20.23 286 22.50 292 0.153 *.sup.)median
Table 1 shows the median dosage of estradiol and progesterone until
day of life 14 for the premature babies of both groups. Both
emulsions resulted in a similarly high hormone supply. While the
emulsion according to the invention was fed constantly with 15
ml/kg/day, the emulsion of the prior art was administered as a
median of 18.8 ml/kg/day (min-max: 11.4 to 25.8 ml/kg/day).
[0064] With the emulsion according to the invention, significantly
higher plasma levels for estradiol could be achieved in the
premature babies (p=0.00038). However, no significant difference
was found in the progesterone plasma levels, when the complete
period of 14 days is considered. The plasma concentrations in the
premature babies treated with the different emulsions were compared
with each other at the individual measuring times (day 1, 3, 7, 14)
(FIGS. 1 and 2). It was found that significantly higher plasma
levels were achieved with an emulsion according to the invention
after 24 hours for both estradiol and progesterone. The median
plasma levels of estradiol achieved on day 3, 7 and 14 with the
latter emulsion were always above the values achieved with the
prior art emulsion. The lower limit of the sought plasma levels of
estradiol (2000 pg/ml) and progesterone (300 ng/ml) was achieved or
exceeded with the emulsion according to the invention in 91% and
46% of all cases, respectively, while with the prior art emulsion,
it was achieved or exceeded in only 64% and 43% of all cases,
respectively.
[0065] Already after 24 hours, the plasma levels of both hormones
were significantly higher for the substitution with the emulsion
according to the invention as compared to the prior art emulsion,
which is a progress towards the aim of reaching the plasma levels
found in the womb as quickly as possible.
[0066] To conclude, the available data indicate an improved
availability of estradiol and progesterone as measured by the
plasma levels reached in premature babies. Thus, the emulsion
according to the invention is more suitable for application with
premature babies as compared to the corresponding prior art
emulsion which was prepared by mixing the hormones with the
finished emulsion.
* * * * *